Twenty-five years after the discovery of the CFTR gene and identification of its functions, we lack answers to many crucial questions, current treatments are inadequate, and cystic fibrosis (CF) remains a life shortening, lethal disease. A major barrier to progress has been lack of a CF animal model other than the mouse. Project leaders in this PPG developed the ferret and pig models of CF to overcome this impediment. Remarkably, these models develop lung disease with many similarities to that of human babies with CF. In this Program four senior and highly accomplished investigators and their teams will seize the unique opportunity to use CF ferrets and pigs as tools to investigate novel episomal and integrating gene transfer vectors. They will test the efficacy of gene transfer in correcting key physiologic defects that arise from loss of CFTR function. Studies with gene transfer vectors will be complemented by novel transgenic ferret and pig models expressing CFTR in a cell type specific or inducible manner. Program scientists will use several novel surrogate endpoints developed in the PPG to probe relationships between CFTR function and correction of biological and pathophysiological endpoints to judge efficacy. They will be guided by how complementation of CFTR function modifies airway biology, including Cl- and HCO3 - transport, host defense and mucociliary transport. The Project Leaders have an outstanding track record of collaboration in CF research, and here they sharpen their focus to a common goal. Their research is highly creative and is supported by five cores that provide innovative services and infrastructure. Discoveries from this PPG will accelerate development of novel therapies for patients who suffer from this devastating disease.